Naphthiofluorene carboxylic acids



United States Patent '0 NAPHTHIOFLUORENE "C'ARBOXYLIC ACIDS Robert H.Mazur, Evanston, Ill,, assignor, by mesne assignments, to G. -D. Searle& Co., Skokie, 111., a corporation of Delaware Application February 7,1955, Serial No. 486,708

5 Claims. .(Cl. 260-3971) No Drawing.

This invention relates to oxygenated polyhydrodimethylnaphthofluorenedicarboxylic acids and esters, and processes for themanufacture-thereof. More particularly this invention relates tollH-naphtho[2,1-a1fiuorenes of the formula whereinR is H or a lowera'lkyl'radical, X is.a carbonyl CO) .or .hydroxymet'hylene CHOH)radical, and

there is a double "bond between carbons 13 and 13a,'or

than '7.

The subject compounds are derived -from the 'maleic anhydride adduct :of1a r3+acetoxyl'7-(ot-acetoxyvinyl)-1,2,3,4,7,8,9,10,11,12,13,14-dodecahydro 10,13dimethyl-lSH-cyclopentaEaJphenanthrene. Cleavage of the anhydro ringtherein under alkaline conditions provides the hydroxy dicarboxylicacids of this invention, which in turn are appropriately esterified byknown techniques to produce the corresponding alkoxycarbonyl compoundshereinafter claimed. Oppenauer oxidation of these hydroxy esters yieldsthe dioxo esters of my discovery, and these esters are converted to theclaimed dioxo acids by saponification.

The compounds to which this invention relates are valuable because oftheir physiological activity. Whereas the steroid adducts which serve asstarting materials for the instant preparations are characterized bystrongly anti-hypertensive properties, the compositions which proceedtherefrom as here disclosed-the substances defined by the claims of thepresent application-are, surprisingly, possessed of potent pressoractivity.

The instant compounds are relatively insoluble in water but may bedissolved in alcohol and other common organic solvents. The subjectcompounds may be administered in solid form as tablets or capsules;dissolved or suspended in aqueous media, they may be given parenterally.

The following examples will illustrate in detail certain of the acidsand esters which constitute the present invention, and methods whichhave been devised for their preparation. However, the invention is notto be construed as limited thereby, either in spirit or in scope, sinceit will be apparent to those skilled in the art of organic synthesisthat many modifications, both of materials and of methods, may bepracticed without departing from the 2,753,359 TPatented July .3, 1-956purpose and .intent of this disclosure. In the examples hereinafterdetailed, temperatures are given in degrees centigrade EC.) ,andrelative amounts of materials in parts by weigh-t,-except as-otherwisenrztted. Specific rotations refer to the D line of sodium andwere determined in methyl alcohol solution .at .room temperatures.

Example 1 A. 2,7 diacet0xy-1,2,3,4,4a,4b,5,6,6a,8,9,10,10a,11a,- 1117,12hexadecahydr0--#afiwdimethyl 11H -naphth0- .LZJ-a] fluorenesQJO-diczzrboxylic (acid .anhydride..-A eso- .lution of 39 ;parts of3,20diacetoxypregnad.1630- triene-preparable by the method .of .Moifet-tand 'ZWeisblat, .J. Amer. .Ghem. :Soc., :74, 2183 .(.l952)and 40 B;1..2,3,4 4a,4 2,5; b;7, ;9l 4; J TbJZ tadecdhyil'ro 2hyiiroxy-4a,6a-dimefhgyl-7-0x0-1JH-napht'holIZI-d1fluoreneQHO-Hicarboxylfc acid.A suspension of 2 parts of the anhydride of thepreceding Part A of this example in 50 parts of 1N aqueous potassiumhydroxide is heated at 100 C. for 1 hour. Solution occurs in process.The hot reaction mixture is brought to a pH of approximately 1 with 2Nhydrochloric acid, then chilled. The precipitate which forms is removedby filtration and recrystallized from aqueous methyl alcohol to givel,2,3,4,4a,4b,5,6,6a,6b,7,8,9,10,10a,11a,l1b,l2 octadecahydro 2hydroxy-4a,6a-dimethyl-7-oxo-llH-naphtho[2,1-a]fluorene-9,lO-dicarboxylicacid as fine needles, M. P. 315-320 C. (with decomposition), specificrotation +5 The product has the formula COOH HOOC

g cm

Example 2 rene-7-one, has the formula OOOCH:

HaCO O C- Example 3 2,3,4,4a,4b,5,6,6a,6b,7,8,9,10,10a,11a,1111,12,13octa-' decahydro 9,10-dimethxycarb0nyl-4a,6a-dimethyl-11H- naphtho [2,1-a fluorene-2,7-di0ne.0ppenauer oxidation of parts of the ester ofExample 2, dissolved in a mixture of 70 parts of toluene and 38 parts ofcyclohexanone, With a solution of 8 parts of aluminum isopropoxide in 35parts of toluene, by heating at reflux temperatures for 2 hours andsubsequently steam distilling in the presence of 100 parts of 50%aqueous Rochelle salt solution provides the desired x,13-unsaturatedketone as a precipitate (in the distilland) which, twice crystallizedfrom a mixture of benzene and cyclohexane, comes down as tiny needles M.P. 233236 C., specific rotation +87". The 2,3,4,4a,4b,5,6,6a,6b,7,8,9,lO,10a,11a,11b,12,13 octadecahydro- 9,10dimethoxycarbonyl 4a,6a-dimethyl-1lH-naphtho- [2,1-a]fluorene-2,7-di0nethus obtained has the formula COOCH;

Example 4 2,3,4,4a,4b,5,6,6a,6b,7,8,9,10,10a,11a,1117,12,13octadecahydr0-4a,6a-dimethyl-2,7-a'i0x0-11H-naphth0[2,1-a1- fluorene-9,1O-dicarboxylzc acid.-Saponification of the es- 4 ter of Example 3according to the technique detailed in Example 1B affords pure2,3,4,4a,4b,5,6,6a,6b,7,8,9,10, 10a,1la,11b,12,13octadecahydro-4a,6a-dimethyl-2,7-di- 0x0llH-naphtho[2,l-alfluorene-9,IO-dicarboxylic acid having the formula C OOH HO O O What is claimed is: 1. A compound of the formula X c o 0 R \JROOC wherein R is selected from the group consisting of hydrogen andmethyl radicals, X is selected from the group consisting of carbonyl andhydroxymethylene radicals, and the carbon atom at 13a is doubly bondedto a carbon selected from the group consisting of the C1 and C13 atoms.

2. 1,2,3,4,4a,4b,5,6,6a,6b,7,8,9,10,10a,11a,1111,12 octadecahydro2-hydroxy-4a,6a-dimethyl-7-oxo-1lH-naph- No references cited.

1. A COMPOUND OF THE FORMULA